Functional expression of CLIFAHDD and IHPRF pathogenic variants of the NALCN channel in neuronal cells reveals both gain- and loss-of-function properties

Abstract The excitability of neurons is tightly dependent on their ion channel repertoire. Among these channels, the leak sodium channel NALCN plays a crucial role in the maintenance of the resting membrane potential. Importantly, NALCN mutations lead to complex neurodevelopmental syndromes, includi...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Malik Bouasse, Hathaichanok Impheng, Zoe Servant, Philippe Lory, Arnaud Monteil
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2019
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/dcd140aae78142bb86ff1ce05531546b
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:dcd140aae78142bb86ff1ce05531546b
record_format	dspace
spelling	oai:doaj.org-article:dcd140aae78142bb86ff1ce05531546b2021-12-02T15:08:47ZFunctional expression of CLIFAHDD and IHPRF pathogenic variants of the NALCN channel in neuronal cells reveals both gain- and loss-of-function properties10.1038/s41598-019-48071-x2045-2322https://doaj.org/article/dcd140aae78142bb86ff1ce05531546b2019-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-019-48071-xhttps://doaj.org/toc/2045-2322Abstract The excitability of neurons is tightly dependent on their ion channel repertoire. Among these channels, the leak sodium channel NALCN plays a crucial role in the maintenance of the resting membrane potential. Importantly, NALCN mutations lead to complex neurodevelopmental syndromes, including infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF) and congenital contractures of limbs and face, hypotonia and developmental delay (CLIFAHDD), which are recessively and dominantly inherited, respectively. Unfortunately, the biophysical properties of NALCN are still largely unknown to date, as well as the functional consequences of both IHPRF and CLIFAHDD mutations on NALCN current. Here we have set-up the heterologous expression of NALCN in the neuronal cell line NG108-15 to investigate the electrophysiological properties of NALCN carrying representative IHPRF and CLIFAHDD mutations. Several original properties of the wild-type (wt) NALCN current were retrieved: mainly carried by external Na+, blocked by Gd3+, insensitive to TTX and potentiated by low external Ca2+ concentration. However, we found that this current displays a time-dependent inactivation in the −80/−40 mV range of membrane potential, and a non linear current-voltage relationship indicative of voltage sensitivity. Importantly, no detectable current was recorded with the IHPRF missense mutation p.Trp1287Leu (W1287L), while the CLIFAHDD mutants, p.Leu509Ser (L509S) and p.Tyr578Ser (Y578S), showed higher current densities and slower inactivation, compared to wt NALCN current. This study reveals that heterologous expression of NALCN channel can be achieved in the neuronal cell line NG108-15 to study the electrophysiological properties of wt and mutants. From our results, we conclude that IHPRF and CLIFAHDD missense mutations are loss- and gain-of-function variants, respectively.Malik BouasseHathaichanok ImphengZoe ServantPhilippe LoryArnaud MonteilNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-14 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Malik Bouasse Hathaichanok Impheng Zoe Servant Philippe Lory Arnaud Monteil Functional expression of CLIFAHDD and IHPRF pathogenic variants of the NALCN channel in neuronal cells reveals both gain- and loss-of-function properties
description	Abstract The excitability of neurons is tightly dependent on their ion channel repertoire. Among these channels, the leak sodium channel NALCN plays a crucial role in the maintenance of the resting membrane potential. Importantly, NALCN mutations lead to complex neurodevelopmental syndromes, including infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF) and congenital contractures of limbs and face, hypotonia and developmental delay (CLIFAHDD), which are recessively and dominantly inherited, respectively. Unfortunately, the biophysical properties of NALCN are still largely unknown to date, as well as the functional consequences of both IHPRF and CLIFAHDD mutations on NALCN current. Here we have set-up the heterologous expression of NALCN in the neuronal cell line NG108-15 to investigate the electrophysiological properties of NALCN carrying representative IHPRF and CLIFAHDD mutations. Several original properties of the wild-type (wt) NALCN current were retrieved: mainly carried by external Na+, blocked by Gd3+, insensitive to TTX and potentiated by low external Ca2+ concentration. However, we found that this current displays a time-dependent inactivation in the −80/−40 mV range of membrane potential, and a non linear current-voltage relationship indicative of voltage sensitivity. Importantly, no detectable current was recorded with the IHPRF missense mutation p.Trp1287Leu (W1287L), while the CLIFAHDD mutants, p.Leu509Ser (L509S) and p.Tyr578Ser (Y578S), showed higher current densities and slower inactivation, compared to wt NALCN current. This study reveals that heterologous expression of NALCN channel can be achieved in the neuronal cell line NG108-15 to study the electrophysiological properties of wt and mutants. From our results, we conclude that IHPRF and CLIFAHDD missense mutations are loss- and gain-of-function variants, respectively.
format	article
author	Malik Bouasse Hathaichanok Impheng Zoe Servant Philippe Lory Arnaud Monteil
author_facet	Malik Bouasse Hathaichanok Impheng Zoe Servant Philippe Lory Arnaud Monteil
author_sort	Malik Bouasse
title	Functional expression of CLIFAHDD and IHPRF pathogenic variants of the NALCN channel in neuronal cells reveals both gain- and loss-of-function properties
title_short	Functional expression of CLIFAHDD and IHPRF pathogenic variants of the NALCN channel in neuronal cells reveals both gain- and loss-of-function properties
title_full	Functional expression of CLIFAHDD and IHPRF pathogenic variants of the NALCN channel in neuronal cells reveals both gain- and loss-of-function properties
title_fullStr	Functional expression of CLIFAHDD and IHPRF pathogenic variants of the NALCN channel in neuronal cells reveals both gain- and loss-of-function properties
title_full_unstemmed	Functional expression of CLIFAHDD and IHPRF pathogenic variants of the NALCN channel in neuronal cells reveals both gain- and loss-of-function properties
title_sort	functional expression of clifahdd and ihprf pathogenic variants of the nalcn channel in neuronal cells reveals both gain- and loss-of-function properties
publisher	Nature Portfolio
publishDate	2019
url	https://doaj.org/article/dcd140aae78142bb86ff1ce05531546b
work_keys_str_mv	AT malikbouasse functionalexpressionofclifahddandihprfpathogenicvariantsofthenalcnchannelinneuronalcellsrevealsbothgainandlossoffunctionproperties AT hathaichanokimpheng functionalexpressionofclifahddandihprfpathogenicvariantsofthenalcnchannelinneuronalcellsrevealsbothgainandlossoffunctionproperties AT zoeservant functionalexpressionofclifahddandihprfpathogenicvariantsofthenalcnchannelinneuronalcellsrevealsbothgainandlossoffunctionproperties AT philippelory functionalexpressionofclifahddandihprfpathogenicvariantsofthenalcnchannelinneuronalcellsrevealsbothgainandlossoffunctionproperties AT arnaudmonteil functionalexpressionofclifahddandihprfpathogenicvariantsofthenalcnchannelinneuronalcellsrevealsbothgainandlossoffunctionproperties
_version_	1718388031278284800

Functional expression of CLIFAHDD and IHPRF pathogenic variants of the NALCN channel in neuronal cells reveals both gain- and loss-of-function properties

Ejemplares similares